2-Amino[1,2,4]triazolo[1,5-c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure-Activity Relationships of Potent Adenosine Receptor Antagonists.

2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A(3)AR antagonists were discovered, including 3,5-di-phenyl[1,2,4]triazolo[4,3-c]quinazoline (17, K-i human A3AR 1.16 nm) and 5'-phenyl-1,2-dihydro-3'H-spiro[indole-3,2'[1,2,4]triazolo[1,5-c] quinazolin]-2-one (20, K-i human A3AR 6.94 nm). In addition, multitarget antagonists were obtained, such as the dual A1/A3 antagonist 2,5-diphenyl[1,2,4] triazolo[1,5-c]quinazoline (13b, K-i human A(1)AR 51.6 nm, human A(3)AR 11.1 nm), and the balanced pan-AR antagonists 5-(2-thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 c, K-i human A(1)AR 131 nm, A(2A)AR 32.7 nm, A(2B)AR 150 nm, A(3)AR 47.5 nm) and 9-bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11q, K-i human A(1)AR 67.7 nm, A(2A)AR 13.6 nm, A(2B)AR 75.0 nm, A(3)AR 703 nm). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species.